FIELD OF THE INVENTION
The anthracycline antibiotics doxorubicin and daunorubicin possess outstanding antitumor activity and are recognized as two of the most important cancer chemotherapeutic drugs available. However, these drugs are quite toxic. In addition to producing stomatitis, alopecia and bone marrow depression, they often cause severe cumulative and irreversible cardiac toxicity which can be fatal. ##STR1##
Numerous investigators have attempted to design related drugs which maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.
Random screening of a vast number of compounds provided by the Allied Chemical Company, at the National Cancer Institute led to the discovery of ametantrone as having significant antitumor activity. Further investigation by Cheng regarding the rational development of analogs of ametantrone through structure-activity studies of some substituted aminoalkyl aminoanthraquinones led to the synthesis of mitoxantrone which exhibited marked antitumor activity. An independent development of mitoxantrone has also been reported by Murdock.
Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In vitro screening systems showed mitoxantrone to have higher efficacy than doxorubicin at equivalent concentrations. In clinical studies, mitoxantrone has ben,shown to be effective against numerous types of tumors with far less toxic side effects than those resulting from doxorubicin therapy.
Mitoxantrone is currently gaining an important place in the clinical management of leukemias and lymphomas as well as in combination therapy of advanced breast and ovarian cancers. Although mitoxantrone is endowed with an improved tolerability profile compared with doxorubicin and other anthracyclines, this drug is not devoid of significant toxic side effects, especially those associated with myelosuppression and cardiotoxicity. Moreover, congestive heart failure is a serious clinical concern, particularly in patients previously treated with anthracyclines. (Faulds, D.; Balfour, J. A.; Chrisp, P.; Langtry, H. D., Mitoxantrone, a Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in the Chemotherapy of Cancer, Drugs 1991, 41, 400-449).
The mechanisms of action of ametantrone and mitoxantrone are not yet well defined. Many studies suggest that intercalation into DNA is a major cellular event. This intercalative interaction may serve as an anchor for the drugs at specific base pair sites of the DNA followed by the critical cell-killing events. Nucleic acid compaction and interference with the DNA topoisomerase II activity resulting in protein associated-DNA strand breaks have also been proposed as critical, events (common also to a number of other antineoplastic agents) which lead to mitoxantrone induced cell death. Cellular destruction by antitumor anthracene-9,10-diones, including mitoxantrone, has also been attributed to oxidative metabolism which results in the formation of free radicals capable of DNA alkylation and/or DNA scission, yielding non-protein associated DNA strand breaks. Recent studies suggest that enzymes such as NADPH (quinone acceptor) oxidoreductase can reduce mitoxantrone to reactive hydroxyl radicals. However, it is generally believed that quinone reduction is probably more related to the cardiotoxic side effects of mitoxantrone than to the mechanism of its antitumor activity. The cardiotoxicity of mitoxantrone and doxorubicin has also been associated with the metal chelating ability of the adjacent hydroxyl and quinone groups. Formation of drug-metal complexes could enhance oxidation-reduction cycling by a metal catalyzed type reaction.
Non-hematological side effects from mitoxantrone treatment are mild compared to side effects of doxorubicin treatment. Although mitoxantrone shows diminished cardiotoxicity when compared to doxorubicin, clinical trials indicate that mitoxantrone is not totally free of cardiotoxicity.
The cardiotoxic effects of the anthracyclines and the anthracene diones are probably multimodal. One important effect is thought to be the peroxidation of cell membrane lipids; the lower incidence of cardiotoxicity associated with mitoxantrone than with doxorubicin is ascribed to the diminished rate of superoxide radical O.sub.2..sup.- formation. The metabolic reduction of mitoxantrone, by NADPH in human liver, to the free radical occurs at a low enough rate that it does not result in a significant increase in microsomal O.sub.2..sup.- formation.
Significant evidence has accumulated which strongly suggests anthracycline semiquinone free radicals and oxygen radicals as major contributors to cardiac toxicity. Many anticancer agents containing a quinone group have been found to be enzymatically reduced to the semiquinone free radical by NADPH-cytochrome reductase. The semiquinone is then incorporated into a redox cycle which involves further catalytic NADPH oxidation and oxygen consumption. Molecular oxygen is reduced by the semiquinone free radical to superoxide anion radicals which can go on to form hydroxyl radicals. Superoxide anion radicals and other reactive oxygen species including hydrogen peroxide, singlet oxygen and hydroxyl radicals are well known to attack unsaturated membrane lipids resulting in lipid peroxidation. This lipid peroxidation is believed to be the cause of anthracycline induced cardiotoxicity. The cardiac tissue is particularly susceptible to damage by lipid peroxidation because cardiac tissue contains lower levels of several enzymes (catalase, superoxide dismutase, and glutathione peroxidase) involved in protection against such damage.
The potential chemotherapeutic utility of mitoxantrone which was evident from the in vivo trial results has warranted further development with the drug. A number of structurally modified analogs of mitoxantrone have since been synthesized and structure-activity relationship studies made.